Gallbladder disease (GBD) is a common, economically burdensome digestive disease. An estimated 20 million Americans are affected with GBD, and more than 700,000 cholecystectomies are performed every year. Its risk factors include age, sex, obesity, type 2 diabetes, and the metabolic syndrome (MS). Ethnic differences, familial aggregation of GBD, and the identification of Lith loci for gallstone disease using animal models suggest genetic influences on GBD. Since the major susceptibility loci for GBD in human populations have not been identified, we recently performed a genome-wide search for susceptibility loci for GBD, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS) and multipoint linkage analysis. After accounting for the covariate effects of age, sex, and MS, we found strong linkage signals for symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. The major goal of this revised competing renewal proposal is to conduct a systematic screening of the 1.5-LOD support interval regions surrounding the two linked regions on chromosome 1p to find the potential functional variant(s) that could relate to our initial linkage findings. We will use a phase-wise single nucleotide polymorphism (SNP) typing strategy to ultimately identify the potential functional variant(s) that influence GBD. Firstly (Aim 1), to cover the two linked regions (~9.5 and ~18 Mb long regions) at high density, but gene-centrically, 4,608 SNPs (~1,600 SNPs in the first region and ~3,000 SNPs in the second) will be typed using high-throughput genotyping procedures and our data (N = 735). The patterns of linkage disequilibrium will be measured, and association analysis with GBD will be performed to prioritize 5 positional candidate genes. These genes will be thoroughly screened by sequencing 150 founders [representing 300 genomes] from SAFDGS families (Aim 2a). After evaluating the genetic variation within these 5 candidate genes, ~250 SNPs will be selected for typing in our samples to perform Bayesian quantitative trait nucleotide (BQTN) analysis in order to identify the most likely functional variants (Aim 2b). Approximately 400 individuals from 10 San Antonio Family Heart Study (SAFHS) families will be recalled as part of a replication sample for this study, and information on GBD phenotypes will be collected (Aim 3a). Selected SNPs that are most strongly associated with GBD in the SAFDGS sample (Aim 2b) will be validated in this replication sample (Aim 3b). This study will lead to identification of genetic factors that influence GBD in Mexican Americans, the fastest growing minority population in the US. These observations could contribute to understanding health disparities among the US populations.Gallbladder disease (GBD) is one of the most prevalent and expensive digestive diseases. The findings from this research project will lead to the identification of genes that influence variation in GBD in Mexican Americans. Ultimately, the proposed research activities may pave the way for prevention and treatment of GBD. PUBLIC HEALTH RELEVANCE: Gallbladder disease (GBD) is one of the most prevalent and expensive digestive diseases. The findings from this research project will lead to the identification of genes that influence variation in GBD in Mexican Americans. Ultimately, the proposed research activities may pave the way for prevention and treatment of GBD.